KAT2A succinyltransferase activity-mediated 14-3-3ζ upregulation promotes β-catenin stabilization-dependent glycolysis and proliferation of pancreatic carcinoma cells Publication date: 28 January 2020 Source: Cancer Letters, Volume 469 Author(s): Yingying Tong, Dong Guo, Dong Yan, Chunmin Ma, Fei Shao, Yugang Wang, Shudi Luo, Liming Lin, Jingjing Tao, Yuhui Jiang, Zhimin Lu, Dongming Xing Abstract Frequently occurring histone lysine succinylation is a newly identified histone modification that can be regulated by KAT2A histone succinyltransferase, which is also a histone acetyltransferase. KAT2A histone succinyltransferase activity is important for tumorigenesis; however, the mechanism underlying this tumor-promoting effect remains elusive. Here we demonstrate that KAT2A is highly expressed in human pancreatic ductal adenocarcinoma (PDAC) specimens and positively correlated with advanced stages of PDAC and short patients’ survival. In addition, KAT2A expression in PDAC specimens is correlated with 14-3-3ζ expression, and KAT2A regulates H3K79 succinylation in the promoter region of YWHAZ (encoding for 14-3-3ζ) to promote YWHAZ mRNA and 14-3-3ζ expression, thereby preventing β-catenin degradation. Expression of succinyltransferase activity-defective KAT2A Y645A reduces H3K79 succinylation and 14-3-3ζ expression, leading to decreased β-catenin stability and subsequently decreased expression of cyclin D1, c-Myc, GLUT1, and LDHA. KAT2A-mediated 14-3-3ζ and β-catenin expression promotes glycolysis, cell proliferation, and migration and invasion of PDAC cells with epithelial-to-mesenchymal transition. These findings reveal a novel and instrumental role of KAT2A-mediated histone succinylation in regulation of gene expression and β-catenin stability to promote tumor cell proliferation and invasion.

Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer Publication date: 28 January 2020 Source: Cancer Letters, Volume 469 Author(s): Mark Bates, Fiona Furlong, Michael F. Gallagher, Cathy D. Spillane, Amanda McCann, Sharon O'Toole, John J. O'Leary Abstract MAD2 is an intriguing protein, which has been associated with poor survival in cancer. Depending on the organ-specific cancer, either high expression or low expression levels have been correlated with low survival rates in patients. MAD2 is also a marker of contradiction. The normal function of MAD2 is to accumulate at kinetochores and generate a wait signal preventing the cell from progressing to anaphase of the cell cycle until the spindle microtubules have correctly aligned with the kinetochores on each chromosome. This process ensures that sister chromatids segregate correctly into each new daughter cell upon cellular division. Thus, the correct function of MAD2 and this crucial cell cycle checkpoint, the spindle assembly checkpoint (SAC), is essential for faithful replicative cell division, the prevention of chromosomal abnormalities and the development of cancer. Surprisingly when MAD2 is supressed for example through siRNA, this results in the induction of cellular senescence or cell cycle arrest. This is an inherent contradiction as normally the dispersement of MAD2 would signal to a cell that they should proceed to anaphase as spindle microtubules have correctly aligned with each chromatid for cell division. In the inverse setting; a second contradiction, high MAD2 expression in cancer patients generally correlates with abnormal chromosome number. However, in normal cells high expression of MAD2 would limit this by generating a wait signal to prevent the cell from proceeding through the cell cycle. In this review article we aim to make sense of the MADness and review the current knowledge of MAD2 and its role in cancer.

Reduction of circular RNA Foxo3 promotes prostate cancer progression and chemoresistance to docetaxel Publication date: 1 January 2020 Source: Cancer Letters, Volume 468 Author(s): Zhiyuan Shen, Le Zhou, Chao Zhang, Jun Xu Abstract Dysregulation of circular RNA Foxo3 (circFoxo3) has been reported to be involved in breast cancer and non-small lung cancer progression. However, little is known about the role of circFoxo3 in prostate cancer, which the present study seeks to investigate. CircFoxo3 expression was analyzed in 22 low-grade prostate cancer samples, 24 high-graded prostate cancer samples, and 18 normal prostate tissues, finding that its quantity was significantly decreased in high-graded compared to low-grade prostate cancer and normal prostate tissues. CircFoxo3 inhibited prostate cancer cell survival, migration, invasion and chemoresistance to docetaxel, which was related to circFoxo3's repression of Foxo3 and EMT. Silencing circFoxo3 expression promoted prostate cancer cell survival, migration, invasion and chemoresistance to docetaxel, as well as the positive effects of androgen on prostate cancer viability. Delivery of circfoxo3 enhanced chemosensitivity to docetaxel of prostate tumor-bearing mice and prolonged the life span of mice, while reduction with siRNAs promoted chemoresistance to docetaxel and shorted the life span of the tumor-bearing mice. Targeting circFoxo3/Foxo3/EMT may provide an applicable strategy for exploring potential prognostic and therapeutic approaches for prostate cancer.

The combination of BET and PARP inhibitors is synergistic in models of cholangiocarcinoma Publication date: 1 January 2020 Source: Cancer Letters, Volume 468 Author(s): Samuel C. Fehling, Aubrey L. Miller, Patrick L. Garcia, Rebecca B. Vance, Karina J. Yoon Abstract Our previous finding that the BET inhibitor (BETi) JQ1 increases levels of the DNA damage marker γH2AX suggested that JQ1 might enhance the sensitivity of tumor cells to PARP inhibitors (PARPi), which are selectively toxic to cells that harbor relatively high levels of DNA damage. To address this hypothesis, we evaluated the effect of a BETi (JQ1 or I-BET762) combined with a PARPi (olaparib or veliparib) in KKU-055 and KKU-100 cholangiocarcinoma (CCA) cell lines and of JQ1 with olaparib in a xenograft model of CCA. Each combination was more effective than any of the four drugs as single agents. Combination indices ranged from 0.1 to 0.8 at the ED50 for all combinations, indicating synergy and demonstrating that synergy was not limited to a specific combination. Mechanistically, downregulation of BETi molecular targets BRD2 or BRD4 by shRNA sensitized CCA cells to BETi as single agents as well as to the combination of a BETi + a PARPi. Our data indicate that combinations of a BETi with a PARPi merit further evaluation as a promising strategy for CCA.

Endogenous production of C–C motif chemokine ligand 2 by nasopharyngeal carcinoma cells drives radioresistance-associated metastasis Publication date: 1 January 2020 Source: Cancer Letters, Volume 468 Author(s): Shan-Shan Guo, Rui Liu, Yue-Feng Wen, Li-Ting Liu, Li Yuan, Yan-Xian Li, Yang Li, Wen-Wen Hao, Jing-Yun Peng, Dan-Ni Chen, Qing-Nan Tang, Xue-Song Sun, Ling Guo, Hao-Yuan Mo, Chao-Nan Qian, Mu-Sheng Zeng, Jin-Xin Bei, Shu-Yang Sun, Qiu-Yan Chen, Lin-Quan Tang Abstract Patients with recurrent nasopharyngeal carcinoma (NPC) have more co-existing distant metastasis than those of no-recurrence and are more likely to suffer distant metastasis after re-irradiation than patients with newly diagnosed NPC. However, the relationship between radioresistance and distant metastasis and the mechanisms involved in radioresistance-associated metastasis are still unclear. In this study, we proved that C–C motif chemokine ligand 2 (CCL2) expression was significantly elevated in HONE1-IR cells and recurrent NPC tumour. Inhibition of CCL2 enhanced sensitivity to radiotherapy in NPC cells. Moreover, autocrine CCL2 promoted NPC cell adaptive radioresistance, metastasis and epithelial-mesenchymal transition. Additionally, p53 activated CCL2 transcription. High CCL2 expression was highly associated with poorer locoregional recurrence free survival, progression free survival and overall survival in patients with newly diagnosed NPC. Notably, high CCL2 expression was an independent prognostic factor for distant metastasis free survival in recurrent NPC patients. Our results provide insights into the autocrine signalling mechanisms of CCL2 and suggest that inhibition of autocrine CCL2 may be a candidate treatment strategy for management of radioresistant NPC.

SOX9/miR-203a axis drives PI3K/AKT signaling to promote esophageal cancer progression Publication date: 1 January 2020 Source: Cancer Letters, Volume 468 Author(s): Lianghai Wang, Zhiyu Zhang, Xiaodan Yu, Qihang Li, Qian Wang, Aimin Chang, Xiaoxi Huang, Xueping Han, Yangguang Song, Jianming Hu, Lijuan Pang, Jun Hou, Feng Li Abstract Deregulation of SOX9 in esophageal cancer has been reported. However, the regulatory mechanisms underlying SOX9 during esophageal squamous cell carcinoma (ESCC) progression remain poorly understood. Here, we independently confirmed the increased SOX9 expression in two ESCC cohorts and its correlation with poor prognosis. We demonstrated that SOX9 was required for maintaining self-renewal, motility, and chemoresistance in vitro and that ectopic expression of SOX9 promoted tumorigenicity in vivo. Screening for potential SOX9-regulated miRNAs revealed that target genes of differentially expressed miRNAs were enriched in the PI3K/AKT signaling pathway and identified the downregulated miR-203a as a candidate. Mechanistically, SOX9 activation caused repression of miR-203a transcription by binding to miR-203a promoter, thus preventing the miR-203a-mediated inhibition of multiple PI3K/AKT/mTOR components, including PIK3CA, AKT2, and RPS6KB1. The association between SOX9 expression and PI3K/AKT/mTOR signaling was further validated in clinical samples. Moreover, rapamycin treatment attenuated the SOX9-mediated malignant phenotypes and potentiated cisplatin-mediated inhibition of tumor growth. Together, these findings uncover a novel activation of the PI3K/AKT pathway by the SOX9/miR-203a axis and define a subgroup of patients who may benefit from targeted therapy.

Epidemiology of lung cancer and lung cancer screening programs in China and the United States Publication date: 1 January 2020 Source: Cancer Letters, Volume 468 Author(s): Dawei Yang, Yang Liu, Chunxue Bai, Xiandong Wang, Charles A. Powell Abstract Lung cancer is a heterogeneous disease that is impacted by environmental exposures and by constitutional genetic or epigenetic susceptibilities to disease development and progression. The United States and China have distinct and diverse populations and geographic environmental exposures that contribute to unique patterns of lung cancer incidence and mortality. In this paper, the authors compare trends of incidence and mortality of lung cancer in the US and China, and the impact on lung cancer screening programs in the two countries. It is worth noting that the mortality of lung cancer in the US has decreased gradually while in China it is still increasing over recent years. While decreasing smoking prevalence and the impact of clean air legislation have helped to mitigate the trend in the US relative to China, the increasingly widespread implementation of lung cancer chest CT screening is expected to impact lung cancer incidence and mortality in both countries. Currently there are few studies to compare the environmental and genetic risk factors for US and Chinese populations with regards to lung cancer incidence and mortality. The authors discuss the impact of gender and exposure risks, mainly smoking and environmental pollutants. Of high importance is the incidence of lung cancer in never smokers that is significantly higher in China than in the United States; this is particularly notable in women. These data suggest inclusion of ambient air pollution exposure and gender into lung cancer risk prognostic models to better capture high-risk individuals, especially for non-smoking women.

Communication between EMT and PD-L1 signaling: New insights into tumor immune evasion Publication date: 1 January 2020 Source: Cancer Letters, Volume 468 Author(s): Yuanyuan Jiang, Hanxiang Zhan Abstract Immune checkpoint blockage has been considered a breakthrough in cancer treatment, achieving encouraging anti-tumor effects in some advanced solid malignancies. However, low response rate and therapeutic resistance represent significant challenges in this field. In addition to its typical role in embryonic development and tissue fibrosis, epithelial-mesenchymal transition (EMT) plays a pivotal role in tumor immunosuppression and immune evasion. Previous studies revealed that EMT is associated with activation of different immune checkpoint molecules, including PD-L1. EMT-induced immune escape promotes cancer progression and may also provide a platform for discovery of novel therapeutic approaches and predictive biomarkers for checkpoint inhibitor therapeutic response. Here, we summarize recent findings focused on EMT-induced immune suppression and evasion in the tumor microenvironment (TME). EMT transcription factors (EMT-TFs), immune cells, cell plasticity and their regulatory role in the immune response are thoroughly reviewed. Bidirectional regulation between EMT and PD-L1 signaling is discussed in terms of cancer immune escape and possible combined therapies. Additionally, we investigated the value of preclinical or clinical trials using EMT targeted therapy combined with PD-L1 inhibitors. This review may help to further understand the role of EMT and PD-L1 signaling in cancer immune evasion. Meanwhile, additional molecular mechanistic studies and clinical trials are urgently needed.

Liquid biopsy in ovarian cancer using circulating tumor DNA and cells: Ready for prime time? Publication date: 1 January 2020 Source: Cancer Letters, Volume 468 Author(s): Du-Bois Asante, Leslie Calapre, Melanie Ziman, Tarek M. Meniawy, Elin S. Gray Abstract Liquid biopsies hold the potential to inform cancer patient prognosis and to guide treatment decisions at the time when direct tumor biopsy may be impractical due to its invasive nature, inaccessibility and associated complications. Specifically, circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) have shown promising results as companion diagnostic biomarkers for screening, prognostication and/or patient surveillance in many cancer types. In ovarian cancer (OC), CTC and ctDNA analysis allow comprehensive molecular profiling of the primary, metastatic and recurrent tumors. These biomarkers also correlate with overall tumor burden and thus, they provide minimally-invasive means for patient monitoring during clinical course to ascertain therapy response and timely treatment modification in the context of disease relapse. Here, we review recent reports of the potential clinical value of CTC and ctDNA in OC, expatiating on their use in diagnosis and prognosis. We critically appraise the current evidence, and discuss the issues that still need to be addressed before liquid biopsies can be implemented in routine clinical practice for OC management.

The influence of patient sex on clinical approaches to malignant glioma Publication date: 1 January 2020 Source: Cancer Letters, Volume 468 Author(s): Silvia Matteoni, Claudia Abbruzzese, Veronica Villani, Walter Malorni, Andrea Pace, Paola Matarrese, Marco G. Paggi Abstract Gliomas are tumors that originate from the glial tissue, thus involving the central nervous system with varying degrees of malignancy. The most aggressive and frequent form is glioblastoma multiforme, a disease characterized by resistance to therapies, frequent recurrences, and extremely poor median survival time. Data on overall glioma case studies demonstrate clear sex disparities regarding incidence, prognosis, drug toxicity, clinical outcome, and, recently, prediction of therapeutic response. In this study, we analyze data in the literature regarding malignant glioma, mainly glioblastoma multiforme, focusing on epidemiological and clinical evaluations. Less discussed issues, such as the role of viral infections, energy metabolism, and predictive aspects concerning the possible use of dedicated therapeutic approaches for male or female patients, will be reported together with different estimated pathogenetic mechanisms underlying astrocyte transformation and glioma chemosensitivity. In this era, where personalized/precision medicine is the most important driver for targeted cancer therapies, the lines of evidence discussed herein strongly suggest that clinical approaches to malignant glioma should consider the patient's sex. Furthermore, retrospectively revising previous clinical studies considering patient sex as a crucial variable is recommended.